Tissue distribution, excretion, and metabolism of 1,2,7,8-tetrachlorodibenzo-p-dioxin in the rat☆
Introduction
Polychlorinated dioxins are part of the larger family of polyhalogenated aromatic hydrocarbons (PAH), which are known environmental pollutants produced unintentionally by human activities. 2,3,7,8-tetrachlorodibenzo-p-dioxin (2378-TCDD) is the most toxic member of the family, which includes 75 chlorinated congeners. The toxicity of 2378-TCDD is thought to be mediated by the cytosolic aryl hydrocarbon receptor (AhR). The biochemical events following 2378-TCDD binding to the AhR and the subsequent toxicity are the subject of intense investigation.
Greater detail about the metabolism of 2378-TCDD is desirable, but very difficult to obtain because the high toxicity (LD50=60 μg/kg for rats) and low metabolic turnover make conventional metabolism studies impractical. Chlorine substitution on the lateral positions (carbons 2, 3, 7, and 8) leads to lower metabolic turnover. The half-life of 2378-TCDD varies from 15 days in the hamster (Neal et al., 1982), 31 days in the rat (Pohjanvirta et al., 1990), to 5.8 yr in man (Poiger and Schlatter, 1986). The data that has been accumulated implicates the liver-inducible monooxygenase, CYP1A2, as a 2378-TCDD protein-binding species Voorman and Aust, 1987, Kedderis et al., 1993, Santostefano et al., 1997. These data explain the dose-dependent hepatic retention of 2378-TCDD at levels in excess of what one would expect based on physicochemical properties alone.
Previous in vivo metabolism studies have used doses ranging from 1 ng/kg to 380 μg/kg of 2378-TCDD from which metabolites were isolated. High performance liquid chromatography (HPLC) and thin layer chromatography (TLC) retention behavior, compared to the parent compound, were used to detect metabolite formation. Low quantities of metabolites detected in the bile were characterized by enzymatic hydrolysis, derivatization, and GC/MS analysis. NIH-shifted, arene-oxide-mediated hydroxylation and ring cleavage reactions were observed.
As part of our laboratory’s research into investigating dioxins in mammalian systems, we elected to study a non-toxic (Schecter, 1994) and, presumably, more highly metabolized dioxin congener, i.e., 1,2,7,8-tetrachlorodibenzo-p-dioxin (1278-TCDD) in the rat. Dosing at mg/kg level would permit a greater mass from which to isolate metabolites. The intact metabolites from urine, bile, and feces could be subjected to analytical techniques such as negative ion fast atom bombardment (−FAB) mass spectrometry and 1H-NMR for complete stereochemical analysis. To our knowledge, no previous metabolism studies have been conducted with non-toxic dioxins, despite the fact that they are also environmental contaminants, and the same route of mammalian exposure would be expected as has been described for the toxic congeners.
Section snippets
Chemicals
[UL 7,8-ring 14C]1278-TCDD was purchased from ChemSyn Science Laboratories (Lenexa, KS, USA; 98% purity). Radiochemical purity was assessed by silica TLC (50:50 hexane:methylene chloride). Unlabeled 1278-TCDD was synthesized in-house by standard methods (Gray et al., 1976), and used to dilute the radiolabel until the desired specific activity was achieved. The dose was dissolved in peanut oil and administered as a single oral dose. A series of standard monohydroxylated tetrachlorodibenzo-p
Results
Each experiment demonstrated that 1278-TCDD was readily excreted by the male rat. Total excretion in the urine, feces, and bile at 72 h ranged from 79% to 94% (Table 1). The half-life of elimination of 1278-TCDD was therefore less than 2 days. The major route of elimination was the feces under all experimental conditions. No significant differences were observed with the conventional study when a lower dose (1 mg/kg) was administered (data not shown). Total fecal elimination in the CONV and GF
Discussion
The data demonstrate that the non-toxic dioxin congener, 1278-TCDD, is rapidly eliminated from male rats (Table 1). The vast majority of the 14C (>78%) of each experimental protocol was eliminated in 72 h. Feces and bile were the major routes for elimination, while urine was a minor elimination route. Very low cumulative tissue retention was observed at 72 h (<5% of the dose; Table 2). GI tract, carcass, and liver were the only tissues with greater than 0.1% of the dose. A dose dependency for
Acknowledgements
The authors wish to acknowledge the technical assistance of Margaret Lorentzsen in providing the mass spectral data; Colleen Pfaff and Barbara Magelky in the preparation of tissue samples.
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